Genome-Wide Association and Admixture Mapping of Benign Ethnic Neutropenia (BEN) in African Americans: CRGGH in collaboration with Dr. Griffin Rodgers lab in NIDDK is conducting genome-wide scan the genome of over 1200 African Americans to shed light on the genetic basis of BEN. Genetic Epidemiology of Metabolic Disorders in African Americans: CRGGH conducted Genome Wide Association Studies (GWAS) in a sample of over 2,000 African Americans to shed light on the clustering of metabolic disorders such hypertension, obesity, insulin resistance, type 2 diabetes (T2D), dyslipidemia and kidney function. The first GWAS in African Americans was conducted by CRGGH in the HUFS. We identified 6 SNPs for blood pressure in or near the genes PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. SLC24A4 and CACNA1H are potential targets for BP regulation. We participated in the largest international GWAS consortia for BP (Nature. Oct 6 2011). CRGGH contributed to several international T2D consortia, including the Meta-analysis of T2D in Africa Americans (MEDIA) Consortium, in which the meta-analysis of 17 GWAS for T2D in over 8,000 cases and 16,000 controls has been performed. Genetics of dyslipidemia: In contrast to the increased prevalence of hypertension, T2D, and obesity observed with increasing degree of westernization, there is remarkable similarity in the distribution of serum lipid parameters across populations of the African Diaspora. In the US, interethnic differences in serum lipid distributions are consistently observed, with African Americans having a generally healthier lipid profile, characterized by lower TG and higher HDL, than European Americans. These results are found despite differences in lifestyle factors that would be expected to produce a worse lipid profile among AA. To shed light on these observations, we evaluated 5 lipid candidate genes to identify variants with ethnicity-specific effects. We sequenced ABCA1, LCAT, LPL, PON1, and SERPINE1 in 48 AA individuals with extreme serum lipid concentrations. Identified variants were genotyped in 1694 and tested for an association with serum lipids. We observed significant ethnic specific effects on HDL and TG. Genetic Epidemiology of Metabolic Disorders in Africans: The Africa America Diabetes Mellitus (AADM) study which has enrolled over 6,000 cases of T2D and controls uses the genome-wide association and linkage approaches to search for susceptibility genes for diabetes. The AADM study has been extremely successful with several publications in high impact journals. For example, the AADM study, in collaboration with deCODE Genetics, made significant contribution in 2007 to the global understanding of the genetic basis of diabetes by identify one of the most consistently replicated gene (TCF7L2) for T2D. CRGGH has completed the genotyping of 2,400 Africans with diabetes and controls to conduct the first GWAS in Africans for T2D. Analysis of this unique data is ongoing. CRGGH has completed whole-exome sequencing of 20 African American families with multiple affected persons and 20 West African families with at least 4 affected family members. Data analysis is ongoing. CRGGH investigators are co-applicant of the newly funded project entitled Burden, Spectrum and Etiology of T2D in sub Saharan Africa. This five-year 3M Wellcome Trust H3Africa award is funding a consortium of 16 centers in 9 African countries, the UK, and the US to enroll 12,000 T2D cases and 12,000 controls. Statistical Approaches and Methods Development: CRGGH investigators are internationally recognized expertise in the analysis of complex traits in admixed African Americans and other African Diaspora populations, as exemplified by a recent invited review on mapping disease-associated variants in admixed populations published in Genome Biology and an American Society of Human Genetics 2010 invited session Complex Disease Genetics Research in Admixed Populations. We have also developed tools that respond to the changing resources and challenges of the field as a whole: novel approaches for the simultaneous analysis of common and rare variants, approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes, and a test for gene-gene interactions in case-control studies. Pharmacogenomics: We have generated a database of pharmacogenomically-relevant gene variants by mining the 1000 Genomes database and conducting de novo genotyping in the NHGRI Microarray Core using the Affymetrix ADME gene chip in 19 global populations sampled from 5 continents (Africa, North and South America, Europe and Asia) for a total of 1,478 persons. We showed that the use of general descriptors (white, black, and Asian), groupings that refer to a social construct, is inappropriate in terms of health decisions. In collaboration with Shawneequa Callier, J.D. of George Washington University, we are studying physician assumptions on genetics and race/ethnicity in the treatment of hypertensive AA on Medicare. Genetic Epidemiology of Podoconiosis: Podoconiosis (Podo) is a devastating, stigmatizing, and neglected tropical disease characterized by lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. It is entirely preventable by wearing shoes. Not all exposed persons develop the disease, and we have shown that Podo is highly heritable (h2 63%). So far, research projects conducted by our team have shed light on the clinical staging of Podo; the economic, ethical, and social issues surrounding the implementation of genomic research in resource-poor settings; the use of genetic information to improve primary prevention strategies; and the genetic basis of Podo (NEJM 2011). African Genome Variation Project (AGV): In collaboration with investigators at the Sanger Institute (UK) and institutions across Africa, weve established the AGV project. This project used the Illumina 2.5M chip to genotype 100 individuals from each of 18 ethnic groups from Africa. CRGGH investigators are analyzing generated data with the promise of informing genomic studies in Africa by providing a reference for allelic, haplotype, and LD structure for common variants in populations not covered by HapMap and the 1000 Genomes projects. Understanding Human History: Using genome-wide genotype data from 3,528 individuals sampled from 163 human ethno-linguistic groups around the world, we identified 19 global ancestral components that tracked geography or linguistic groupings, both well-known barriers to gene flow. We observed that 94.4% of individuals had mixed ancestry, with profound implications for understanding human evolutionary history and health. Genome-wide studies of adaptation in African ancestry populations: The genetic, ecological, and socio-cultural diversities of Africans promise to contribute to the global understanding of human adaptive history. We performed a genome-wide analysis for evidence of recent positive selection in a sample of 120 individuals of Wolaita ethnicity belonging to Omotic speaking people in comparison to the 11 HapMap populations. We found signals of recent positive selection in several HLA loci unique to the Wolaita population. We also found selection signals in PPAR-alpha, a gene involved in energy metabolism during prolonged food deficiency. Our findings suggest that pathogen burden, diet, and high-altitude hypoxia were strong selective forces. Societal Implications of Genomic Research: CRGGH pays particular attention to the documentation and description of the non-random pattern of human genetic variation and its link to disease risks in different populations. By engaging in constructive conversations on these issues, we are contributing to the untangling of the complexities of genetic variation within the context of health disparities and group identity (NEJM 2010; BMC Medical Genomics 2009).